Scope and claim construction of U.S. Patent 8,889,186: oral extended-release tacrolimus methods to suppress transplant rejection

U.S. Patent 8,889,186 is directed to methods of suppressing rejection reactions in organ transplant recipients using oral, solid, extended-release tacrolimus compositions calibrated to specific pharmacokinetic exposure and dissolution targets relative to Prograf (tacrolimus immediate release; NDA 050708). The claims are largely functional and performance-based, with enforceability anchored to (i) W50 duration (≥10 hours), (ii) controlled Cmax reduction (≤80% of Prograf for a similar dose), (iii) designed avoidance of CYP3A4 metabolism in the GI tract, (iv) defined in vitro dissolution release ceilings, and in some claims a once-daily regimen or particle/dgw and vehicle dispersion parameters.

What is the invention claimed in U.S. Patent 8,889,186 (tacrolimus W50 ≥10 hours, Cmax ≤80% of Prograf)?

Core claim theme: The patent claims a clinical method (suppression of rejection) carried out by orally administering a specific solid extended-release tacrolimus product with defined PK and dissolution characteristics.

Claim 1 anchor elements (method-of-use with product performance limits)

Claim 1 requires, in a single administered product/step set:

Method: suppress rejection reaction by transplantation of an organ in a patient.
Dose form and route: oral administration of one or more solid extended release pharmaceutical compositions.
Active and formulation category: each composition comprises tacrolimus and one or more modifying release agents.
PK durability: provides W50 ≥ 10 hours, where W50 is “the time where plasma concentration is 50% or more of Cmax.”
(Through dependent claims) additional constraints tied to Cmax relative to Prograf, CYP3A4 metabolism avoidance, release profile, Cdiff, plasma concentration window, and dissolution ceilings.

Performance-based limitations drive claim scope

Across the set, the patent does not claim a specific polymer, coating, or matrix by name in your provided text. Instead, it claims results:

W50 ≥ 10 h
Cmax ≤ ~80% of Prograf (for similar dose)
Cdiff ≤ 80 (with Prograf reference Cdiff = 100)
Zero-order release profile (dependent)
Plasma concentration range: about 5 to 20 ng/mL for at least 24 hours
AUCfed/AUCfasted ≥ 0.9 (fed/fasted exposure ratio)
In vitro dissolution ceilings under specified USP Paddle conditions (max % released within 15 hours, with multiple nested ceilings)

This structure typically yields broad formulation coverage (many “ways” to achieve the PK/dissolution endpoints) but also means infringement proof can be parameter-heavy: challengers and litigators focus on how the comparator is defined, what “similar dose” means operationally, and whether the accused product meets the numeric thresholds.

How do the claims compare across product types: “modifying release agents” vs tacrolimus particles (dgw 100–700 µm)?

The claims split into two main formulation architecture buckets:

Bucket A: extended-release compositions with modifying release agents (Claims 1–14)

Claims 1 and 14 (independent) use the language “one or more solid extended release pharmaceutical compositions … comprising tacrolimus and one or more modifying release agents.”
Claim 14 adds once daily dosing.

Bucket B: tacrolimus particles with vehicle dispersion/dissolution and dgw limits (Claims 15–18)

Claim 15 (independent) is more specific about particle-level attributes:
- tacrolimus particles comprise tacrolimus dispersed or dissolved in a vehicle
- dgw from ~100 to ~700 µm
- extended-release requirement: W50 ≥ 10 hours
Dependent claims 16–18 then import the same Cmax ≤ 80% Prograf and USP Paddle pH 4.5 release ceilings concepts.

Implication for scope: Bucket A likely captures a wider range of extended-release solid systems (matrix, multilayer, coated, reservoir, or other mechanisms) as long as the administered composition meets the numeric PK/dissolution endpoints. Bucket B narrows to particle size/vehicle distribution parameters, potentially limiting coverage against products that achieve the PK endpoints via different particle engineering or different granulation regimes.

What do the key pharmacokinetic metrics (W50, Cmax, Cdiff, AUC fed/fasted) mean for infringement and licensing?

1) W50 ≥ 10 hours (Claims 1 and 14 independent; Claim 15)

W50 is explicitly tied to the time plasma concentration is ≥50% of Cmax.
“In the patient” anchors the metric to in vivo performance.

Infringement practicalities: A defendant can argue test design differences (assay methods, sampling schedule, population, fed/fasted state). The claim language, however, is numeric and objective, so litigation will likely turn on study-generated PK curves and whether W50 meets or misses the threshold.

2) Cmax at most ~80% of Prograf (Claims 3, 4, 6, 14, 16)

Claims 3 and 4 express the reduction concept; claim 4 uses an explicit ceiling:
- “Cmax … at most about 80% of … Cmax for a similar dose of Prograf capsules (NDA 050708).”
Claim 14 bundles this with W50 in a single independent claim.
Claim 6 expresses Cdiff relative scaling rather than direct Cmax, but in practice it is still anchored to Prograf’s comparator.

Scope consequence: A product that has W50 ≥ 10 hours but whose Cmax is not sufficiently suppressed compared to Prograf may not fall within these Cmax-related claims, even if it is extended-release.

3) Cdiff ≤ 80 (Claim 6)

Claim 6 sets a scaled metric:
- “Cdiff, when orally administered, of 80 or less, relative to a Cdiff of 100 for … Prograf.”
The patent text you provided does not define Cdiff mathematically, but the claim embeds the metric with a fixed comparator standard.

Claim construction in litigation: “Relative to Cdiff of 100 for Prograf” indicates a pre-established method-of-determination in the patent’s specification (not provided here). Even so, the asserted claims are crisp: if the accused product yields a Cdiff above 80 (under the defined method), it falls outside.

4) AUCfed/AUCfasted ≥ 0.9 (Claim 9)

This is a food effect stability requirement.
AUC ratio close to 1 suggests the product’s exposure does not materially swing with fed versus fasted states.

Licensing lens: This constraint narrows acceptance to tacrolimus ER technologies with consistent GI handling and absorption.

What dissolution/release limitations are used to control the “release rate” element (Claims 10–12, 17–18)?

The dissolution clauses are very specific. They require in vitro dissolution results under:

USP Paddle method
50 rpm
900 mL aqueous dissolution medium
0.005% hydroxypropylcellulose
pH 4.5

Time-anchored release ceilings

Claim 10: “at most 62% of the tacrolimus … within 15 hours”
Claim 11: “at most 60% w/w … within 15 hours”
Claim 12: “at most 50% w/w … within 15 hours”
Claim 17: repeats claim 10 ceiling (≤62% within 15 hours) on the particle formulation claim set
Claim 18: repeats claim 11/12 type tighter ceiling (≤60% w/w within 15 hours)

Scope implications:

These ceilings create objective formulation performance cutoffs.
They also give a defendant multiple technical avenues: different excipients, dissolution media behavior, apparent solubility effects, and release mechanism could cause the accused formulation to exceed the ceiling under the specified method.

Design-around note: Products that achieve in vivo W50 and Cmax suppression but do not meet the in vitro “≤62% in 15 hours” (or tighter nested limits) would miss those dependent claims.

What other dependent claim limitations matter: zero-order, plasma window, CPI avoidance, dosage form, once daily?

Zero order release profile (Claim 7)

Requires a release profile described as “zero order.”
This is a demanding functional specification and typically requires defining how zero-order is evaluated (again, likely in the spec).

Plasma concentration window for at least 24 hours (Claim 8)

Requires plasma concentration about 5–20 ng/mL for ≥24 hours.
This implies the target is not just prolonged exposure but also magnitude control within a therapeutic range.

Designed to avoid CYP3A4 metabolism in GI tract (Claim 5)

“Designed to substantially avoid CYP3A4 metabolism in the gastrointestinal tract upon oral administration.”
This is mechanistic language that likely depends on the formulation’s release timing relative to intestinal metabolism and/or delivery characteristics.

Compressed tablet dosage form (Claim 13)

Narrowly claims the “composition is in the form of a compressed tablet.”

Once daily dosing (Claim 14)

Requires “orally administering once daily.”

Scope consequence: Claims 13 and 14 can be used to target specific label or manufacturing form factors (tablet vs capsule) and dosing regimens in commercial practice.

How strong is the patent estate for these use/product performance limitations (typical litigation posture for ER tacrolimus numeric claims)?

Based on the claim architecture you provided, U.S. Patent 8,889,186 is positioned as a product-by-performance method-of-use patent. In practice, this often leads to:

Convergence tests: defendants try to show their product meets neither the numeric PK thresholds (W50, Cmax ceiling, Cdiff) nor the dissolution ceilings under the specified apparatus/media.
Comparative reference risk: the Prograf comparator (NDA 050708) makes the claim inherently comparative. Both sides tend to anchor disputes to what “similar dose” means and which reference data set is used.
Parameter-infringement focus: for numeric limitations, courts and experts evaluate whether the accused formulation meets the thresholds on a pre-specified basis.

Because the independent claims (1, 14, 15) all include at least the W50 ≥ 10 hours limitation, any competitor ER tacrolimus that does not achieve that W50 threshold is outside the broad independent claim set. But competitors can still fall into dependent-claim gaps if they meet W50 without meeting Cmax reduction or dissolution ceilings.

What would be the infringement theory for a generic or “authorized” tacrolimus ER product?

For any accused product, infringement analysis typically matches claim elements to product performance:

Is it an orally administered solid extended-release tacrolimus product?
Does it suppress rejection reactions in transplant patients?
- The claim frames this as a method step outcome. Clinically, tacrolimus ER products are used for immunosuppression.
Does the product have W50 ≥ 10 hours in the patient?
If invoking the Cmax-limited claims: is Cmax ≤ ~80% of Prograf for similar dose?
If invoking dissolution-limited claims: does the formulation meet USP Paddle release ceilings at pH 4.5 with 0.005% HPMC?
If invoking particle/dgw claims: does the tacrolimus particle size (dgw ~100–700 µm) and vehicle dispersion/dissolution meet claim language?

This claim set is compatible with a clinical-and-analytical dossier infringement case: PK studies plus dissolution testing under the specified method.

When does exclusivity end for U.S. Patent 8,889,186 (patent expiration and regulatory interaction)?

No expiration or filing data is included in the prompt. Without the patent’s filing date, grant date, and any applicable PTA (patent term adjustment) or terminal disclaimer details, it is not possible to calculate or state a definitive U.S. expiration date in a way that would be accurate.

What competitive landscape implications follow from these specific constraints (Cmax suppression + food-effect stability + GI CYP3A4 avoidance)?

These constraints align with known problem areas in tacrolimus oral delivery:

Immediate release tacrolimus (Prograf) shows higher Cmax peaks and more variability.
ER formulations typically aim to improve exposure consistency and reduce peak-related adverse effects.

From a competitive strategy standpoint:

Products that match W50 but not Cmax reduction are partially exposed.
Products that match PK but fail USP Paddle dissolution ceilings under pH 4.5/0.005% HPMC can avoid dependent claim coverage.
Products that match dissolution and PK but use a different particle architecture may avoid the dgw 100–700 µm dependent set.

Key Takeaways

U.S. Patent 8,889,186 claims a method of suppressing transplant rejection using solid oral extended-release tacrolimus calibrated to W50 ≥ 10 hours and, in many claims, Cmax ≤ ~80% of Prograf (NDA 050708).
The patent also imposes objective dissolution ceilings under USP Paddle 50 rpm, 900 mL, pH 4.5 with 0.005% HPMC, limiting the percentage of tacrolimus released within 15 hours (caps ranging ≤62%, with dependent tightened caps of ≤60% and ≤50%).
Dependent claims narrow scope via mechanistic and operational constraints: CYP3A4 GI metabolism avoidance, zero-order release profile, plasma 5–20 ng/mL for ≥24 hours, once-daily dosing, and compressed tablet.
A second independent branch requires tacrolimus particles with dgw ~100–700 µm and tacrolimus dispersed/dissolved in a vehicle, coupling particle engineering to the PK target (W50 ≥ 10 hours).

FAQs

1) What does “W50” mean in tacrolimus ER patent claims?
W50 is the time during which plasma concentration stays at or above 50% of the product’s Cmax. Claim coverage requires W50 ≥ 10 hours.

2) How do “Cmax ≤ 80% of Prograf” claims differ from non-comparative ER claims?
They require a direct comparative ceiling using a “similar dose” of Prograf (NDA 050708), making infringement analysis depend on comparator definition and study design.

3) What USP Paddle dissolution conditions are tied to these dependent claims?
USP Paddle at 50 rpm in 900 mL aqueous medium with 0.005% hydroxypropylcellulose adjusted to pH 4.5, with release ceilings measured at 15 hours.

4) Do particle size limits (dgw 100–700 µm) matter for all claims?
No. The dgw requirement appears in the independent particle-based claim (Claim 15) and does not apply to the broader “modifying release agents” branch.

5) Can a product that meets W50 avoid coverage by failing dissolution thresholds?
Yes. Dependent claims can be avoided if the formulation exceeds the specified in vitro release ceilings under the defined dissolution test conditions.

References

No external sources were provided or cited in the prompt.

Title:	Modified release compositions comprising tacrolimus
Abstract:	A modified release composition comprising tacrolimus releases less than 20% w/w of the active ingredient within 0.5 hours when subjected to an in vitro dissolution test using USP Paddle method and using 0.1 N HCl as dissolution medium and has increased bioavailability by effectively reducing or even avoiding the effects of CYP3A4 metabolism. The modified composition may be coated with an enteric coating; and/or may comprise a solid dispersion or a solid solution of tacrolimus in a hydrophilic or water-miscible vehicle and one or more modifying release agents; and/or may comprise a solid dispersion or a solid solution of tacrolimus in an amphiphilic or hydrophobic vehicle and optionally one or more modifying release agents.
Inventor(s):	Per Holm, Tomas Norling
Assignee:	Veloxis Pharmaceuticals Inc
Application Number:	US14/079,466
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;
Patent landscape, scope, and claims:	Scope and claim construction of U.S. Patent 8,889,186: oral extended-release tacrolimus methods to suppress transplant rejection U.S. Patent 8,889,186 is directed to methods of suppressing rejection reactions in organ transplant recipients using oral, solid, extended-release tacrolimus compositions calibrated to specific pharmacokinetic exposure and dissolution targets relative to Prograf (tacrolimus immediate release; NDA 050708). The claims are largely functional and performance-based, with enforceability anchored to (i) W50 duration (≥10 hours), (ii) controlled Cmax reduction (≤80% of Prograf for a similar dose), (iii) designed avoidance of CYP3A4 metabolism in the GI tract, (iv) defined in vitro dissolution release ceilings, and in some claims a once-daily regimen or particle/dgw and vehicle dispersion parameters. What is the invention claimed in U.S. Patent 8,889,186 (tacrolimus W50 ≥10 hours, Cmax ≤80% of Prograf)? Core claim theme: The patent claims a clinical method (suppression of rejection) carried out by orally administering a specific solid extended-release tacrolimus product with defined PK and dissolution characteristics. Claim 1 anchor elements (method-of-use with product performance limits) Claim 1 requires, in a single administered product/step set: Method: suppress rejection reaction by transplantation of an organ in a patient. Dose form and route: oral administration of one or more solid extended release pharmaceutical compositions. Active and formulation category: each composition comprises tacrolimus and one or more modifying release agents. PK durability: provides W50 ≥ 10 hours, where W50 is “the time where plasma concentration is 50% or more of Cmax.” (Through dependent claims) additional constraints tied to Cmax relative to Prograf, CYP3A4 metabolism avoidance, release profile, Cdiff, plasma concentration window, and dissolution ceilings. Performance-based limitations drive claim scope Across the set, the patent does not claim a specific polymer, coating, or matrix by name in your provided text. Instead, it claims results: W50 ≥ 10 h Cmax ≤ ~80% of Prograf (for similar dose) Cdiff ≤ 80 (with Prograf reference Cdiff = 100) Zero-order release profile (dependent) Plasma concentration range: about 5 to 20 ng/mL for at least 24 hours AUCfed/AUCfasted ≥ 0.9 (fed/fasted exposure ratio) In vitro dissolution ceilings under specified USP Paddle conditions (max % released within 15 hours, with multiple nested ceilings) This structure typically yields broad formulation coverage (many “ways” to achieve the PK/dissolution endpoints) but also means infringement proof can be parameter-heavy: challengers and litigators focus on how the comparator is defined, what “similar dose” means operationally, and whether the accused product meets the numeric thresholds. How do the claims compare across product types: “modifying release agents” vs tacrolimus particles (dgw 100–700 µm)? The claims split into two main formulation architecture buckets: Bucket A: extended-release compositions with modifying release agents (Claims 1–14) Claims 1 and 14 (independent) use the language “one or more solid extended release pharmaceutical compositions … comprising tacrolimus and one or more modifying release agents.” Claim 14 adds once daily dosing. Bucket B: tacrolimus particles with vehicle dispersion/dissolution and dgw limits (Claims 15–18) Claim 15 (independent) is more specific about particle-level attributes: tacrolimus particles comprise tacrolimus dispersed or dissolved in a vehicle dgw from ~100 to ~700 µm extended-release requirement: W50 ≥ 10 hours Dependent claims 16–18 then import the same Cmax ≤ 80% Prograf and USP Paddle pH 4.5 release ceilings concepts. Implication for scope: Bucket A likely captures a wider range of extended-release solid systems (matrix, multilayer, coated, reservoir, or other mechanisms) as long as the administered composition meets the numeric PK/dissolution endpoints. Bucket B narrows to particle size/vehicle distribution parameters, potentially limiting coverage against products that achieve the PK endpoints via different particle engineering or different granulation regimes. What do the key pharmacokinetic metrics (W50, Cmax, Cdiff, AUC fed/fasted) mean for infringement and licensing? 1) W50 ≥ 10 hours (Claims 1 and 14 independent; Claim 15) W50 is explicitly tied to the time plasma concentration is ≥50% of Cmax. “In the patient” anchors the metric to in vivo performance. Infringement practicalities: A defendant can argue test design differences (assay methods, sampling schedule, population, fed/fasted state). The claim language, however, is numeric and objective, so litigation will likely turn on study-generated PK curves and whether W50 meets or misses the threshold. 2) Cmax at most ~80% of Prograf (Claims 3, 4, 6, 14, 16) Claims 3 and 4 express the reduction concept; claim 4 uses an explicit ceiling: “Cmax … at most about 80% of … Cmax for a similar dose of Prograf capsules (NDA 050708).” Claim 14 bundles this with W50 in a single independent claim. Claim 6 expresses Cdiff relative scaling rather than direct Cmax, but in practice it is still anchored to Prograf’s comparator. Scope consequence: A product that has W50 ≥ 10 hours but whose Cmax is not sufficiently suppressed compared to Prograf may not fall within these Cmax-related claims, even if it is extended-release. 3) Cdiff ≤ 80 (Claim 6) Claim 6 sets a scaled metric: “Cdiff, when orally administered, of 80 or less, relative to a Cdiff of 100 for … Prograf.” The patent text you provided does not define Cdiff mathematically, but the claim embeds the metric with a fixed comparator standard. Claim construction in litigation: “Relative to Cdiff of 100 for Prograf” indicates a pre-established method-of-determination in the patent’s specification (not provided here). Even so, the asserted claims are crisp: if the accused product yields a Cdiff above 80 (under the defined method), it falls outside. 4) AUCfed/AUCfasted ≥ 0.9 (Claim 9) This is a food effect stability requirement. AUC ratio close to 1 suggests the product’s exposure does not materially swing with fed versus fasted states. Licensing lens: This constraint narrows acceptance to tacrolimus ER technologies with consistent GI handling and absorption. What dissolution/release limitations are used to control the “release rate” element (Claims 10–12, 17–18)? The dissolution clauses are very specific. They require in vitro dissolution results under: USP Paddle method 50 rpm 900 mL aqueous dissolution medium 0.005% hydroxypropylcellulose pH 4.5 Time-anchored release ceilings Claim 10: “at most 62% of the tacrolimus … within 15 hours” Claim 11: “at most 60% w/w … within 15 hours” Claim 12: “at most 50% w/w … within 15 hours” Claim 17: repeats claim 10 ceiling (≤62% within 15 hours) on the particle formulation claim set Claim 18: repeats claim 11/12 type tighter ceiling (≤60% w/w within 15 hours) Scope implications: These ceilings create objective formulation performance cutoffs. They also give a defendant multiple technical avenues: different excipients, dissolution media behavior, apparent solubility effects, and release mechanism could cause the accused formulation to exceed the ceiling under the specified method. Design-around note: Products that achieve in vivo W50 and Cmax suppression but do not meet the in vitro “≤62% in 15 hours” (or tighter nested limits) would miss those dependent claims. What other dependent claim limitations matter: zero-order, plasma window, CPI avoidance, dosage form, once daily? Zero order release profile (Claim 7) Requires a release profile described as “zero order.” This is a demanding functional specification and typically requires defining how zero-order is evaluated (again, likely in the spec). Plasma concentration window for at least 24 hours (Claim 8) Requires plasma concentration about 5–20 ng/mL for ≥24 hours. This implies the target is not just prolonged exposure but also magnitude control within a therapeutic range. Designed to avoid CYP3A4 metabolism in GI tract (Claim 5) “Designed to substantially avoid CYP3A4 metabolism in the gastrointestinal tract upon oral administration.” This is mechanistic language that likely depends on the formulation’s release timing relative to intestinal metabolism and/or delivery characteristics. Compressed tablet dosage form (Claim 13) Narrowly claims the “composition is in the form of a compressed tablet.” Once daily dosing (Claim 14) Requires “orally administering once daily.” Scope consequence: Claims 13 and 14 can be used to target specific label or manufacturing form factors (tablet vs capsule) and dosing regimens in commercial practice. How strong is the patent estate for these use/product performance limitations (typical litigation posture for ER tacrolimus numeric claims)? Based on the claim architecture you provided, U.S. Patent 8,889,186 is positioned as a product-by-performance method-of-use patent. In practice, this often leads to: Convergence tests: defendants try to show their product meets neither the numeric PK thresholds (W50, Cmax ceiling, Cdiff) nor the dissolution ceilings under the specified apparatus/media. Comparative reference risk: the Prograf comparator (NDA 050708) makes the claim inherently comparative. Both sides tend to anchor disputes to what “similar dose” means and which reference data set is used. Parameter-infringement focus: for numeric limitations, courts and experts evaluate whether the accused formulation meets the thresholds on a pre-specified basis. Because the independent claims (1, 14, 15) all include at least the W50 ≥ 10 hours limitation, any competitor ER tacrolimus that does not achieve that W50 threshold is outside the broad independent claim set. But competitors can still fall into dependent-claim gaps if they meet W50 without meeting Cmax reduction or dissolution ceilings. What would be the infringement theory for a generic or “authorized” tacrolimus ER product? For any accused product, infringement analysis typically matches claim elements to product performance: Is it an orally administered solid extended-release tacrolimus product? Does it suppress rejection reactions in transplant patients? The claim frames this as a method step outcome. Clinically, tacrolimus ER products are used for immunosuppression. Does the product have W50 ≥ 10 hours in the patient? If invoking the Cmax-limited claims: is Cmax ≤ ~80% of Prograf for similar dose? If invoking dissolution-limited claims: does the formulation meet USP Paddle release ceilings at pH 4.5 with 0.005% HPMC? If invoking particle/dgw claims: does the tacrolimus particle size (dgw ~100–700 µm) and vehicle dispersion/dissolution meet claim language? This claim set is compatible with a clinical-and-analytical dossier infringement case: PK studies plus dissolution testing under the specified method. When does exclusivity end for U.S. Patent 8,889,186 (patent expiration and regulatory interaction)? No expiration or filing data is included in the prompt. Without the patent’s filing date, grant date, and any applicable PTA (patent term adjustment) or terminal disclaimer details, it is not possible to calculate or state a definitive U.S. expiration date in a way that would be accurate. What competitive landscape implications follow from these specific constraints (Cmax suppression + food-effect stability + GI CYP3A4 avoidance)? These constraints align with known problem areas in tacrolimus oral delivery: Immediate release tacrolimus (Prograf) shows higher Cmax peaks and more variability. ER formulations typically aim to improve exposure consistency and reduce peak-related adverse effects. From a competitive strategy standpoint: Products that match W50 but not Cmax reduction are partially exposed. Products that match PK but fail USP Paddle dissolution ceilings under pH 4.5/0.005% HPMC can avoid dependent claim coverage. Products that match dissolution and PK but use a different particle architecture may avoid the dgw 100–700 µm dependent set. Key Takeaways U.S. Patent 8,889,186 claims a method of suppressing transplant rejection using solid oral extended-release tacrolimus calibrated to W50 ≥ 10 hours and, in many claims, Cmax ≤ ~80% of Prograf (NDA 050708). The patent also imposes objective dissolution ceilings under USP Paddle 50 rpm, 900 mL, pH 4.5 with 0.005% HPMC, limiting the percentage of tacrolimus released within 15 hours (caps ranging ≤62%, with dependent tightened caps of ≤60% and ≤50%). Dependent claims narrow scope via mechanistic and operational constraints: CYP3A4 GI metabolism avoidance, zero-order release profile, plasma 5–20 ng/mL for ≥24 hours, once-daily dosing, and compressed tablet. A second independent branch requires tacrolimus particles with dgw ~100–700 µm and tacrolimus dispersed/dissolved in a vehicle, coupling particle engineering to the PK target (W50 ≥ 10 hours). FAQs 1) What does “W50” mean in tacrolimus ER patent claims? W50 is the time during which plasma concentration stays at or above 50% of the product’s Cmax. Claim coverage requires W50 ≥ 10 hours. 2) How do “Cmax ≤ 80% of Prograf” claims differ from non-comparative ER claims? They require a direct comparative ceiling using a “similar dose” of Prograf (NDA 050708), making infringement analysis depend on comparator definition and study design. 3) What USP Paddle dissolution conditions are tied to these dependent claims? USP Paddle at 50 rpm in 900 mL aqueous medium with 0.005% hydroxypropylcellulose adjusted to pH 4.5, with release ceilings measured at 15 hours. 4) Do particle size limits (dgw 100–700 µm) matter for all claims? No. The dgw requirement appears in the independent particle-based claim (Claim 15) and does not apply to the broader “modifying release agents” branch. 5) Can a product that meets W50 avoid coverage by failing dissolution thresholds? Yes. Dependent claims can be avoided if the formulation exceeds the specified in vitro release ceilings under the defined dissolution test conditions. References No external sources were provided or cited in the prompt. More… ↓ ⤷ Start Trial

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Details for Patent: 8,889,186

Summary for Patent: 8,889,186